Transplantation of allogeneic donor cells, tissues or organs (transplantation between genetically different individuals of the same species) is used to treat a variety of conditions (typically tissue, or organ-failure conditions) and is often the sole or highly preferred therapeutic option. The list of successfully transplanted cells, tissues and organs includes kidney, heart, lung, liver, corneas, pancreas, marrow, skin, and bones. However, allogeneic transplantation involves significant risks and drawbacks, including graft rejection, complications from immunosuppressive therapy and graft-versus host disease which are frequently highly debilitating or lethal.
Rejection of allografts is presently understood to be initiated by the recognition of allogeneic (i.e. donor) major histocompatibility complex (MHC) molecules by recipient T-lymphocytes, leading to upregulated cellular and humoral immunity through activation of T cells. The MHC antigens are typically presented to the recipient T-lymphocytes by antigen presenting cells, such as macrophages and dendritic cells. Although immunosuppressive drugs such as cyclosporine may be used in an attempt to modulate rejection, these immunosuppressive agents have severe side effects and often fail to prevent continued rejection episodes.
Dendritric cells (DCs) are a family of professional antigen presenting cells (APCs) that are present in virtually all tissues of the body. The ability of dendritic cells to capture foreign antigens, migrate to lymphoid tissues and redistribute antigen-MHC to the cell surface along with appropriate costimulatory signals are well known T-cell priming functions for these APCs. In addition to these immunostimulatory properties, dendritic cells are also known to play a role in down-regulating immune responses. Certain subpopulations of dendritic cells, acting as professional APCs, also maintain and regulate T-cell tolerance in the periphery. There is thus a need for therapeutic methods and compositions capable of inducing immunological tolerance with lower toxicity and improved efficacy.